DESCRIPTION: (Applicant's Abstract) The PI has recently developed an ultra-rapid, high-resolution method for the analytical determination of drugs of abuse and related compounds. Based on electrospray ionization with ion mobility separation and mass spectrometric detection, this method separates compounds with resolving powers comparable to traditional chromatographic methods on a millisecond time scale and with detection limits similar to that possible after gas chromatography. In chromatographic terms, theoretical plate numbers larger than 200,000 have been measured in less than a second with concomitant plate heights of 600 nm at detection limits less that 1 ppb (ng/mL). While ion mobility spectrometry has been routinely used for the street detection of volatile drugs of abuse, it has not been compatible with the detection of polar and non-volatile drugs in biological matrices. This grant application proposes to evaluate electrospray/ion mobility spectrometry/mass spectrometry (ESI/IMS/MS) as an analytical method for the rapid and sensitive measurement of drugs of abuse from complex matrixes and as a fundamental research instrument to measure conformational states of opioid and other peptides of interest. The project is divided into three phases, 1) the evaluation of ESI/IMS/MS as a rapid separation and detection device for the quantitative and qualitative determination of drugs of abuse from liquid samples; 2) the evaluation of secondary electrospray ionization/IMS/MS as a method for the determination of drugs of abuse from vapor samples: and 3) conformer characterization and isomer separation of peptides of interest. In addition to a stand-alone device the instrument will be coupled to both liquid and gas chromatography. Successful completion of the project will not only result in an analytical method for the rapid quantification and identification of drugs of abuse, but will also provide a research tool that can be coupled directly to in vivo dialysis experiments or used to obtain highly resolved spatial and temporal drug concentration profiles in extracellular space.